1. Field of the Invention
The invention relates to a process for preparing alkali metal salts of malonic monoalkyl esters by selective (or partial) saponification of malonic dialkyl esters via the intermediate of a CH-acid alkali metal salt.
2. Background of the Invention
Alkali metal salts of malonic monoalkyl esters and, in particular, potassium monoethyl malonate (abbreviated as KEM hereafter) are used as precursors for synthesizing pharmaceuticals having a quinolone structure. The use for syntheses in the pharmaceutical sector makes high demands on product purity.
A synthesis of potassium monoethyl malonate which was described as early as in the last century by van't Hoff (Ber. Dtsch. Chem. Ges., 7, 1572) and which is still currently practiced starts from diethyl malonate (abbreviated as DEM hereafter) which is selectively saponified with potassium hydroxide. According to EP 0 720 981 Al, this is performed using equimolar amounts of starting materials in an alcoholic medium, i.e. using alcoholic potassium hydroxide solution. However, the sought-after selective saponification is achieved only to an inadequate extent, so that only a target product which is considerably contaminated with dipotassium malonate (abbreviated as DKM below) is obtained. The DKM content is usually in the order of magnitude of several % by weight. Removal of the DKM from the KEM, which is necessary for use of the latter as a pharmaceutical precursor, is difficult and includes extensive purification operations.
Another disadvantage with said process is that alcoholic potassium hydroxide solution is not a customary commercial product, but must be prepared from alcohol and solid potassium hydroxide (caustic potash) with dissipation of the heat of solution. The handling and storage of caustic solids, such as caustic potash and caustic soda, in industrial amounts is associated with considerable costs for reasons of health and safety at work. In addition, alcoholic alkali metal hydroxide solutions, in particular those containing alcohols having a chain carbon number &gt;1, generally cannot be stored without the initiation of aging processes which readily lead to product discoloration.
A further disadvantage of the known process is the relatively high dilution at which the process must be carried out. The alcohol is used at 19 to 28 times the amount by weight of potassium hydroxide. This large amount of alcohol has an adverse effect on the space-time yield and increases the expense for recovery of the solvent. The amount of alcohol is further increased by the DEM being used in alcoholic solution.
Box et al., Heterocycles, Vol. 32, No. 2, 1991, 245 ff., mention a synthesis of .beta.-lactones and .beta.-lactams, in which KEM acts as intermediate. In the experimental part, the preparation of KEM from DEM and alcoholic potassium hydroxide solution is described on page 247. The two starting materials are, as in the process of EP 0 720 981 Al already cited, used in equimolar amounts, that is to say each at 100 mmol. The molar ratios of DEM to KOH were calculated wrongly, however, since 20.225 g of DEM are 126 mmol and are equivalent to 1.26 times the molar amount of KOH. If it is further assumed that the potassium hydroxide used had, as is commercially usual, a KOH content of approximately 90% by weight (remainder water), 20.225 g of DEM are actually equivalent to 1.38 times the molar amount of KOH (calculated as 100%). Repeating the work using molar ratios of 1.26:1 and 1.38:1 showed that, although pure KEM containing less than 0.5% by weight of DKM is obtainable by this process, the precipitated KEM was very difficult to filter. In the case of laboratory batches, the filtering time was more than two hours. Such times are prohibitive for production on an industrial scale. In addition, according to Box et al., similarly to the case of the process of said EP 0 720 981 Al, considerable amounts of alcohol are required, and finally the yields of KEM are also not satisfactory.
German patent application 19817101.3 (O.Z. 5297) relates to a process for preparing KEM by selective saponification of DEM with potassium hydroxide, in which the potassium hydroxide is added to the DEM, DEM and potassium hydroxide are used in a molar ratio of at least 1.5 and the potassium hydroxide is distributed effectively in the DEM.
One of the objects of the present invention is to provide a process for preparing alkali metal salts of malonic monoalkyl esters which avoids said disadvantages of the prior art, i.e. without associated use of large amounts of alcohol and without using alcoholic alkali metal hydroxide solution, give high yields of pure low-DKM and readily filterable alkali metal salts of malonic monoalkyl esters. A further object of the invention is to provide a process which is similarly as advantageous as the process of said prior German patent application.